Showing papers by "Johns Hopkins University published in 2009"

A New Equation to Estimate Glomerular Filtration Rate

Abstract: The Modification of Diet in Renal Disease (MDRD) Study equation underestimates glomerular filtration rate (GFR) in patients with mild kidney disease. Levey and associates therefore developed and va...

Finding the missing heritability of complex diseases

Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

The Clavien-Dindo classification of surgical complications: five-year experience.

Abstract: Background and Aims:The lack of consensus on how to define and grade adverse postoperative events has greatly hampered the evaluation of surgical procedures. A new classification of complications, initiated in 1992, was updated 5 years ago. It is based on the type of therapy needed to correct the co

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

Abstract: Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, a...

Five-year wilkinson microwave anisotropy probe observations: cosmological interpretation

Abstract: The Wilkinson Microwave Anisotropy Probe (WMAP) 5-year data provide stringent limits on deviations from the minimal, six-parameter Λ cold dark matter model. We report these limits and use them to constrain the physics of cosmic inflation via Gaussianity, adiabaticity, the power spectrum of primordial fluctuations, gravitational waves, and spatial curvature. We also constrain models of dark energy via its equation of state, parity-violating interaction, and neutrino properties, such as mass and the number of species. We detect no convincing deviations from the minimal model. The six parameters and the corresponding 68% uncertainties, derived from the WMAP data combined with the distance measurements from the Type Ia supernovae (SN) and the Baryon Acoustic Oscillations (BAO) in the distribution of galaxies, are: Ω b h 2 = 0.02267+0.00058 –0.00059, Ω c h 2 = 0.1131 ± 0.0034, ΩΛ = 0.726 ± 0.015, ns = 0.960 ± 0.013, τ = 0.084 ± 0.016, and at k = 0.002 Mpc-1. From these, we derive σ8 = 0.812 ± 0.026, H 0 = 70.5 ± 1.3 km s-1 Mpc–1, Ω b = 0.0456 ± 0.0015, Ω c = 0.228 ± 0.013, Ω m h 2 = 0.1358+0.0037 –0.0036, z reion = 10.9 ± 1.4, and t 0 = 13.72 ± 0.12 Gyr. With the WMAP data combined with BAO and SN, we find the limit on the tensor-to-scalar ratio of r 1 is disfavored even when gravitational waves are included, which constrains the models of inflation that can produce significant gravitational waves, such as chaotic or power-law inflation models, or a blue spectrum, such as hybrid inflation models. We obtain tight, simultaneous limits on the (constant) equation of state of dark energy and the spatial curvature of the universe: –0.14 < 1 + w < 0.12(95%CL) and –0.0179 < Ω k < 0.0081(95%CL). We provide a set of WMAP distance priors, to test a variety of dark energy models with spatial curvature. We test a time-dependent w with a present value constrained as –0.33 < 1 + w 0 < 0.21 (95% CL). Temperature and dark matter fluctuations are found to obey the adiabatic relation to within 8.9% and 2.1% for the axion-type and curvaton-type dark matter, respectively. The power spectra of TB and EB correlations constrain a parity-violating interaction, which rotates the polarization angle and converts E to B. The polarization angle could not be rotated more than –59 < Δα < 24 (95% CL) between the decoupling and the present epoch. We find the limit on the total mass of massive neutrinos of ∑m ν < 0.67 eV(95%CL), which is free from the uncertainty in the normalization of the large-scale structure data. The number of relativistic degrees of freedom (dof), expressed in units of the effective number of neutrino species, is constrained as N eff = 4.4 ± 1.5 (68%), consistent with the standard value of 3.04. Finally, quantitative limits on physically-motivated primordial non-Gaussianity parameters are –9 < f local NL < 111 (95% CL) and –151 < f equil NL < 253 (95% CL) for the local and equilateral models, respectively.

The Seventh Data Release of the Sloan Digital Sky Survey

Abstract: This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11,663 deg^2 of imaging data, with most of the ~2000 deg^2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry on a 120° long, 2°.5 wide stripe along the celestial equator in the Southern Galactic Cap, with some regions covered by as many as 90 individual imaging runs. We include a co-addition of the best of these data, going roughly 2 mag fainter than the main survey over 250 deg^2. The survey has completed spectroscopy over 9380 deg^2; the spectroscopy is now complete over a large contiguous area of the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog, reducing the rms statistical errors at the bright end to 45 milliarcseconds per coordinate. We further quantify a systematic error in bright galaxy photometry due to poor sky determination; this problem is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.

IDH1 and IDH2 Mutations in Gliomas

Abstract: Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

Final Version of 2009 AJCC Melanoma Staging and Classification

Abstract: Purpose To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. Methods The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Results Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm 2 ), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level.

Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement (Chinese edition)

Abstract: Provide a structured summary including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings, systematic review registration number 2 Structured summary

STATs in cancer inflammation and immunity: a leading role for STAT3

Abstract: Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors

Abstract: The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with 18 F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0. Methods: PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors’ experience, draft criteria were formulated for PET tumor response to treatment. Results: Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has

Human Protein Reference Database—2009 update

Abstract: Human Protein Reference Database (HPRD--http://www.hprd.org/), initially described in 2003, is a database of curated proteomic information pertaining to human proteins. We have recently added a number of new features in HPRD. These include PhosphoMotif Finder, which allows users to find the presence of over 320 experimentally verified phosphorylation motifs in proteins of interest. Another new feature is a protein distributed annotation system--Human Proteinpedia (http://www.humanproteinpedia.org/)--through which laboratories can submit their data, which is mapped onto protein entries in HPRD. Over 75 laboratories involved in proteomics research have already participated in this effort by submitting data for over 15,000 human proteins. The submitted data includes mass spectrometry and protein microarray-derived data, among other data types. Finally, HPRD is also linked to a compendium of human signaling pathways developed by our group, NetPath (http://www.netpath.org/), which currently contains annotations for several cancer and immune signaling pathways. Since the last update, more than 5500 new protein sequences have been added, making HPRD a comprehensive resource for studying the human proteome.

Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

Abstract: Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.

New Equations to Estimate GFR in Children with CKD

Abstract: The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.

Advanced Heart Failure Treated with Continuous-Flow Left Ventricular Assist Device

Abstract: Background Patients with advanced heart failure have improved survival rates and quality of life when treated with implanted pulsatile-flow left ventricular assist devices as compared with medical therapy. New continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices. Methods In this randomized trial, we enrolled patients with advanced heart failure who were ineligible for transplantation, in a 2:1 ratio, to undergo implantation of a continuousflow device (134 patients) or the currently approved pulsatile-flow device (66 patients). The primary composite end point was, at 2 years, survival free from disabling stroke and reoperation to repair or replace the device. Secondary end points included survival, frequency of adverse events, the quality of life, and functional capacity. Results Preoperative characteristics were similar in the two treatment groups, with a median age of 64 years (range, 26 to 81), a mean left ventricular ejection fraction of 17%, and nearly 80% of patients receiving intravenous inotropic agents. The primary composite end point was achieved in more patients with continuous-flow devices than with pulsatile-flow devices (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001; hazard ratio, 0.38; 95% confidence interval, 0.27 to 0.54; P<0.001), and patients with continuous-flow devices had superior actuarial survival rates at 2 years (58% vs. 24%, P = 0.008). Adverse events and device replacements were less frequent in patients with the continuous-flow device. The quality of life and functional capacity improved significantly in both groups. Conclusions Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity. (ClinicalTrials.gov number, NCT00121485.)

Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

Abstract: Summary Background Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. Methods In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m 2 per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French–American–British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Findings Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21·1 months (IQR 15·1–26·9), median overall survival was 24·5 months (9·9–not reached) for the azacitidine group versus 15·0 months (5·6–24·1) for the conventional care group (hazard ratio 0·58; 95% CI 0·43–0·77; stratified log-rank p=0·0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50·8% (95% CI 42·1–58·8) of patients in the azacitidine group were alive compared with 26·2% (18·7–34·3) in the conventional care group (p Interpretation Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care. Funding Celgene Corporation.

Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells

Higher versus Lower Positive End-Expiratory Pressures in Patients with the Acute Respiratory Distress Syndrome

Abstract: The members of the Writing Committee background Most patients requiring mechanical ventilation for acute lung injury and the acute res- piratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ven- tilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention. We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients. methods We randomly assigned 549 patients with acute lung injury and ARDS to receive me- chanical ventilation with either lower or higher PEEP levels, which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen. results Mean (±SD) PEEP values on days 1 through 4 were 8.3±3.2 cm of water in the lower- PEEP group and 13.2±3.5 cm of water in the higher-PEEP group (P<0.001). The rates of death before hospital discharge were 24.9 percent and 27.5 percent, respectively (P=0.48; 95 percent confidence interval for the difference between groups, -10.0 to 4.7 percent). From day 1 to day 28, breathing was unassisted for a mean of 14.5±10.4 days in the lower-PEEP group and 13.8±10.6 days in the higher-PEEP group (P = 0.50). conclusions These results suggest that in patients with acute lung injury and ARDS who receive me- chanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical out- comes are similar whether lower or higher PEEP levels are used.

The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores.

Abstract: For the past 25 years, it has been known that alterations in DNA methylation (DNAm) occur in cancer, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a notable overlap (45-65%) of the locations of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.

Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults.

Abstract: Background Obstructive sleep apnea (OSA) is a common chronic disorder that often requires lifelong care. Available practice parameters provide evidence-based recommendations for addressing aspects of care. Objective This guideline is designed to assist primary care providers as well as sleep medicine specialists, surgeons, and dentists who care for patients with OSA by providing a comprehensive strategy for the evaluation, management and long-term care of adult patients with OSA. Methods The Adult OSA Task Force of the American Academy of Sleep Medicine (AASM) was assembled to produce a clinical guideline from a review of existing practice parameters and available literature. All existing evidence-based AASM practice parameters relevant to the evaluation and management of OSA in adults were incorporated into this guideline. For areas not covered by the practice parameters, the task force performed a literature review and made consensus recommendations using a modified nominal group technique. Recommendations Questions regarding OSA should be incorporated into routine health evaluations. Suspicion of OSA should trigger a comprehensive sleep evaluation. The diagnostic strategy includes a sleep-oriented history and physical examination, objective testing, and education of the patient. The presence or absence and severity of OSA must be determined before initiating treatment in order to identify those patients at risk of developing the complications of sleep apnea, guide selection of appropriate treatment, and to provide a baseline to establish the effectiveness of subsequent treatment. Once the diagnosis is established, the patient should be included in deciding an appropriate treatment strategy that may include positive airway pressure devices, oral appliances, behavioral treatments, surgery, and/or adjunctive treatments. OSA should be approached as a chronic disease requiring long-term, multidisciplinary management. For each treatment option, appropriate outcome measures and long-term follow-up are described.

Genetic variation in IL28B and spontaneous clearance of hepatitis C virus

Abstract: Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer.

Abstract: Background Use of computed tomography (CT) for diagnostic evaluation has increased dramatically over the past 2 decades. Even though CT is associated with substantially higher radiation exposure than conventional radiography, typical doses are not known. We sought to estimate the radiation dose associated with common CT studies in clinical practice and quantify the potential cancer risk associated with these examinations. Methods We conducted a retrospective cross-sectional study describing radiation dose associated with the 11 most common types of diagnostic CT studies performed on 1119 consecutive adult patients at 4 San Francisco Bay Area institutions in California between January 1 and May 30, 2008. We estimated lifetime attributable risks of cancer by study type from these measured doses. Results Radiation doses varied significantly between the different types of CT studies. The overall median effective doses ranged from 2 millisieverts (mSv) for a routine head CT scan to 31 mSv for a multiphase abdomen and pelvis CT scan. Within each type of CT study, effective dose varied significantly within and across institutions, with a mean 13-fold variation between the highest and lowest dose for each study type. The estimated number of CT scans that will lead to the development of a cancer varied widely depending on the specific type of CT examination and the patient's age and sex. An estimated 1 in 270 women who underwent CT coronary angiography at age 40 years will develop cancer from that CT scan (1 in 600 men), compared with an estimated 1 in 8100 women who had a routine head CT scan at the same age (1 in 11 080 men). For 20-year-old patients, the risks were approximately doubled, and for 60-year-old patients, they were approximately 50% lower. Conclusion Radiation doses from commonly performed diagnostic CT examinations are higher and more variable than generally quoted, highlighting the need for greater standardization across institutions.

Five-Year Wilkinson Microwave Anisotropy Probe Observations: Data Processing, Sky Maps, and Basic Results

Abstract: The Wilkinson Microwave Anisotropy Probe (WMAP) is a Medium-Class Explorer (MIDEX) satellite aimed at elucidating cosmology through full-sky observations of the cosmic microwave background (CMB). The WMAP full-sky maps of the temperature and polarization anisotropy in five frequency bands provide our most accurate view to date of conditions in the early universe. The multi-frequency data facilitate the separation of the CMB signal from foreground emission arising both from our Galaxy and from extragalactic sources. The CMB angular power spectrum derived from these maps exhibits a highly coherent acoustic peak structure which makes it possible to extract a wealth of information about the composition and history of the universe. as well as the processes that seeded the fluctuations. WMAP data have played a key role in establishing ACDM as the new standard model of cosmology (Bennett et al. 2003: Spergel et al. 2003; Hinshaw et al. 2007: Spergel et al. 2007): a flat universe dominated by dark energy, supplemented by dark matter and atoms with density fluctuations seeded by a Gaussian, adiabatic, nearly scale invariant process. The basic properties of this universe are determined by five numbers: the density of matter, the density of atoms. the age of the universe (or equivalently, the Hubble constant today), the amplitude of the initial fluctuations, and their scale dependence. By accurately measuring the first few peaks in the angular power spectrum, WMAP data have enabled the following accomplishments: Showing the dark matter must be non-baryonic and interact only weakly with atoms and radiation. The WMAP measurement of the dark matter density puts important constraints on supersymmetric dark matter models and on the properties of other dark matter candidates. With five years of data and a better determination of our beam response, this measurement has been significantly improved. Precise determination of the density of atoms in the universe. The agreement between the atomic density derived from WMAP and the density inferred from the deuterium abundance is an important test of the standard big bang model. Determination of the acoustic scale at redshift z = 1090. Similarly, the recent measurement of baryon acoustic oscillations (BAO) in the galaxy power spectrum (Eisenstein et al. 2005) has determined the acoustic scale at redshift z approx. 0.35. When combined, these standard rulers accurately measure the geometry of the universe and the properties of the dark energy. These data require a nearly flat universe dominated by dark energy consistent with a cosmological constant. Precise determination of the Hubble Constant, in conjunction with BAO observations. Even when allowing curvature (Omega(sub 0) does not equal 1) and a free dark energy equation of state (w does not equal -1), the acoustic data determine the Hubble constant to within 3%. The measured value is in excellent agreement with independent results from the Hubble Key Project (Freedman et al. 2001), providing yet another important consistency test for the standard model. Significant constraint of the basic properties of the primordial fluctuations. The anti-correlation seen in the temperature/polarization (TE) correlation spectrum on 4deg scales implies that the fluctuations are primarily adiabatic and rule out defect models and isocurvature models as the primary source of fluctuations (Peiris et al. 2003).

The Bethesda System for Reporting Thyroid Cytopathology.

Abstract: Objective To address terminology and other issues related to thyroid fine-needle aspiration (FNA), the National Cancer Institute (NCI) hosted The NCI Thyroid FNA State of the Science Conference. The conclusions regarding terminology and morphologic criteria from the NCI meeting led to the Bethesda Thyroid Atlas Project and form the framework for the Bethesda System for Reporting Thyroid Cytopathology. Design Participants of the Atlas Project were selected from among the committee members of the NCI FNA State of the Science Conference and other participants at the live conference. The terminology framework was based on a literature search of English language publications dating back to 1995 using PubMed as the search engine; online forum discussions ( http://thyroidfna.cancer.gov/forums/default.aspx ); and formal interdisciplinary discussions held on October 22 and 23, 2007, in Bethesda, MD. Main outcome For clarity of communication, the Bethesda System for Reporting Thyroid Cytopathology recommends that each report begin with one of the six general diagnostic categories. Each of the categories has an implied cancer risk that links it to an appropriate clinical management guideline. Conclusions The project participants hope that the adoption of this framework will facilitate communication among cytopathologists, endocrinologists, surgeons, and radiologists; facilitate cytologic-histologic correlation for thyroid diseases; facilitate research into the understanding of thyroid diseases; and allow easy and reliable sharing of data from different laboratories for national and international collaborative studies.

Circulating Mutant DNA to Assess Tumor Dynamics

Abstract: DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. We apply a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in body samples of patients. Measurements of ctDNA can be used to reliably monitor tumor dynamics in subjects with cancer, especially those who are undergoing surgery or chemotherapy. This personalized genetic approach can be generally applied.

Projected cancer risks from computed tomographic scans performed in the United States in 2007.

Abstract: Methods: Risk models based on the National Research Council’s “Biological Effects of Ionizing Radiation” report and organ-specific radiation doses derived from a national survey were used to estimate age-specific cancer risks for each scan type. These models were combined with age- and sex-specific scan frequencies for the US in 2007 obtained from survey and insurance claims data. We estimated the mean number of radiationrelatedincidentcancerswith95%uncertaintylimits(UL) using Monte Carlo simulations. Results:Overall,weestimatedthatapproximately29000 (95% UL, 15000-45000) future cancers could be related to CT scans performed in the US in 2007. The largest contributions were from scans of the abdomen and pelvis (n=14 000) (95% UL, 6900-25 000), chest (n=4100) (95% UL, 1900-8100), and head (n=4000) (95% UL, 1100-8700), as well as from chest CT angiography (n=2700) (95% UL, 1300-5000). One-third of the projectedcancerswereduetoscansperformedattheages of 35 to 54 years compared with 15% due to scans performed at ages younger than 18 years, and 66% were in females.

c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.

Abstract: Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine, which is highly transported into proliferating cells, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood. Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. This leads to upregulation of glutamine catabolism. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis. The unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.